Zeitschriftenaufsatz
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2023
DNA polymerase θ protects leukemia cells from metabolically induced DNA damage
Autor:in
Vekariya, Umeshkumar; Toma, Monika; Nieborowska-Skorska, Margaret; Le, Bac; Caron, Marie-Christine; Kukuyan, Anna-Mariya; Sullivan-Reed, Katherine; Podszywalow-Bartnicka, P.; Chitrala, Kumara; Atkins, Jessica; Drzewiecka, Malgorzata; Feng, WJ; chan, joe; Chatla, Srinivas; Golovine, Konstantin V.; Jelinek, Jaroslav; Sliwinski, Tomasz; Ghosh, Jayashri; Matlawska-Wasowska, Ksenia; Chandramouly, Gurushankar; Nejati, Reza; Wasik, M. M.; Sykes, Stephen; Piwocka, Katarzyna; Hadzijusufovic, Emir; Valent, Peter; Pomerantz, Richard T.; Morton, George J. P.; Childers, Wayne E.; Zhao, Huaqing; Paietta, Elisabeth M.; levine, ross; Tallman, Martin S.; Fernandez, Hugo; Litzow, Mark; Gupta, Gaorav P.; Masson, Jean Yves; Skorski, Tomasz
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POL theta) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POL theta and its proteasomal degradation. Overexpression of POL theta in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POL theta-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POL theta polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POL theta inhibitor in vitro and in vivo. In conclusion, we demonstrated that POL theta plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.
Schlagwörter
Animals; Mice; BRCA1 Protein; BRCA2 Protein; DNAmetabolism; DNA Damage; Leukemiaenzymologygenetics; DNA Polymerase theta
Dokumententyp
Originalarbeit
ISSN/eISSN
0006-4971 - 1528-0020
10.1182/blood.2022018428
WoS ID
PubMed ID